Process for the production of 6beta:19-oxido-steroids



Patented Oct. 24, 1967 3,349,083 PROCESS FOR THE. PRQDUCTION F 65:19-0XIDO-STEROES Albert Wettstein, Riehen, Georg Anner, Karl Heusler and Jaroslav Kalvoda, Basel, and Hellrnut Ueberwasser, Riehen, Switzerland, assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 7, 1962, Ser. No. 222,207 Claims priority, application Switzerland, July 15, 1960, 8,133/60; Oct. 28, 1960, 12,107/60; Dec. 23, 1960, 14,393/60; Apr. 5, 1961, 3,989/61; June 2, 1961, 6,480/ 61; Jan. 9, 1962, 185/62 7 Claims, (Cl. 260-23955) The present invention relates to a process for the production of ot-halogen-6fl:19-oxido-steroids from 19- unsubstituted '5a-halogen-6fl-hydroxy steroids.

This application is a continuation-in-part of our copending application Ser. No. 122,654, filed July 10, 1961, by Albert Wettstein et al., and now abandoned.

The process of this invention is an important step in a novel and simple conversion of normal steroids into 19-nor-steroids. Since a number of 19-nor-steroids, more especially derivatives of 19-nor-testosterone and of 19- nor-progesterone, are used extensively as anabolic, androgenic, gestagenic and progestational agents a new process for the production of these compounds is of great importance. So far the 19-nor-steroids were available only by a complicated sequence of reactions which involve pyrolytic aromatization of the ring A and subsequent reduction with an alkali metal and ammonia. An alternative synthesis uses a microbiological hydroxylation of the 19-carbon atom followed by elimination of the angular C19-substituent. The yield in the hydroxylation step however is in most cases unsatisfactory. In both known processes the possibilities for variations in substituents in rings B, C and D are very restricted due to the drastic conditions in the pyrolysis step on one hand and to the substrate-specificity of the enzymatic reaction on the other hand.

The new process however gives not only high yield of the desired end products but can be applied to a Wide variety of different steroids since oxo groups, ketalized oxo groups, esterified and etherified hydroxy groups, halogen substituents or double bonds do not interfere in the reactions claimed.

The new process of the present invention consists in treating a 19-unsubstituted 5a-halogeno-6 3-hydroxy-steroid with a heavy metal acylate having an oxidizing action. If desired, the resulting 5a-halogeno-6fizl9-oxidosteroids may be oxidized, if desired, before and/ or after hydrolysis of any acyloxy groups present, oxo groups may be reduced and/ or a hydroxyl, hydrocarbon and/ or A -3-oxo group may be introduced in known manner.

The 6,8:19-oxido-steroids, which are now easy to prepare according to the process of the present invention, enable the 19-norsteroids to be prepared in an extremely simple manner without requiring preliminary aromatization of the ring A. This conversion into the valuable 19- nor-steroids is shown in our copending applications Ser. No. 122,655, now U.S. Patent No. 3,067,198, and Ser. No. 122,656, now U.S. Patent No. 3,077,482, both filed July 10, 1961, by A. Wettstein et al.

It could not be foreseen that the 5a-halogeno-6B-hydroxy-steroids, which are readily accessible from A -steroids by the addition of a hypohalous acid, can be used as starting materials in the process of the present invention, since it was known in the art that such halohydrins are easily dehydrohalogenated to form 5,626,8-oxido-steroids, by the action of metal salts of weak acids, such as alkali metal acetates.

The heavy metal acylate having an oxidizing action, used in the new process, is particularly a lead tetraacylate of aliphatic, cycloaliphatic or aromatic carboxylic acids, containing up to 15 carbon atoms. Especially useful are lead tetra-lower alkanoates, such as lead tetraacetate, lead tetra-propionate or lead tetra-trimethylacetate; furthermore lead tetraacylates of substituted lower alkanoic acids, such as lead tetra-trifiuoroacetate, or of monocyclic carbocyclic aliphatic or aromatic carboxylic acids, such as lead tetrahexahydrobenzoate or lead tetrabenzoate.

The process of the present invention can be carried out, for example, thus: The starting material is dissolved or suspended in a solvent that is inert towards oxidation agents, for example in a hydrocarbon e.g. hexane or benzene, preferably an alicyclic hydrocarbon, such as cyclohexane, methylcyclohexane or dimethylcyclohexane or a halogenated hydrocarbon, preferably a polyhalogen-lower alkane or alkene, such as carbon tetrachloride or hexachloro-butadiene, or mixtures of two or more of said solvents. Hereupon, a lead tetraacylate, such as lead tetraacetate, and a weak base, for example calcium carbonate, are added, and the reaction mixture is then stirred with heating under atmospheric or super-atmospheric pressure. The time taken by the reaction depends on the temperature and/ or on the solvent used. When the reaction is performed with lead tetraacetate in boiling cyclohexane or methyl-cyclohexane, it is in general complete after about 1 /2 to 20 hours.

If desired, the oxygenated 19-methyl group in a 5mhalogen-6fi:19-oxido-steroid obtained by the present process can be further oxidized, for example by treating Sa-halogen-6B: l9-oxido-steroid with a strong oxidant, for example ruthenium tetroxide or preferably with a derivative of hexavalent chromium, such as chromic acid or tertiary butyl chromate, in a solvent such, for example, as a lower fatty acid such as acetic or propionic acid, or in a chlorinated hydrocarbon such as carbon tetrachloride, more especially at an elevated temperature ranging from 50 to C. In this manner, by introducing an oxo group in position 19, there are obtained lactones of 5a-halogen-6B-hydroxy-steroid-19-oic acids.

On the other hand, any acyloxy groups present in the 5a-halogen-6fi:l9-oxido-steroids obtained by the process of the invention, for example in positions 3 and 17 or 20, may be hydrolyzed and the resulting hydroxy compound oxidized to form a 3-ketone, 3:17-diketone or 3:20-diketone. In these 3-ketones a 4:5-double bond can be introduced by dehydrohalogenation performed in known manner, e.g. by treatment with an alkali or with an acid. For the splitting off of hydrogen halide from the '3-oxo-5ahalogen-06B:19-oxido-steroids even mild treatment with an alkali metal acetate or with pyridine suflices.

It is also possible, for example, to react one of the 5u-halogeno-6/3:19-oxido-17-oxo-androstanes obtained ac cording to the process of the invention with an alkylmetal, alkenyl-metal or alkinyl-metal compound, for example with methyl magnesium iodide, methyl lithium, ethyl magnesium iodide, isobutyl lithium, allyl magnesium bromide, methallyl magnesium bromide, sodium-, potassiumor lithium-acetylide, propargyl magnesium bromide, lithium methyl acetylide or the like; in this manner there are obtained (without the Son-halogeno group being affected) the corresponding fill-hydroxy- 17a-alkyl-, alkenylor alkinyl-androstanes. Following upon the reaction with the aforementioned organo-metal compounds a A -3-oxo grouping may be formed in the manner described above.

The resulting A -3:17-dioxo-6,8: l9-oxido-androstenes can be converted in known manner into A -3-oxo-17/3 hydroxy-66:19-oxido-androstenes, for example by selective reduction with a complex metal hydride, such as sodium borohydride, or by reducing both oxo groups, for example with lithium aluminum hydride, to form the 3:17-diol and reoxidation in position 3 with maganese dioxide or with acetone and aluminum isopropylate or tertiary butylate at room temperature. The resulting 6B:19-oxido-testosterones can then be sterified in known manner.

It is also possible to introduce a 1711- and/or 21-hydroxyl group in known manner in a resulting 6fizl9-oxido-20oxo-pregnane, more especially, for example, by enolacetylation to the A -20-acetate, oxidation with a peracid and hydrolysis to form the 17ot-hydroxy-20-ketone. The A -3-oxo grouping can then be formed as described above, before or after introducing a 21-hydroxyl group, for example by bromination, exchange with potassium acetate and hydrolysis.

The side chain of 3B-acetoxy-5a-halogeno-6/3:19-oxidospirostanes can be degraded in known manner, for example by heating with an acid anhydride and subsequent oxidation of the resulting furostene (pseudo-sapogenin), whereby the A -3fi-acetoxy-5a-halogeno-ofl:l9-oxido 20- oxo-pregnenes are obtained.

The 5a-halogen-6[ihydroxy-steroids used as starting materials in the process claimed may belong to the androstane, pregnane, cholane, cholestane, spirostane, stigmastane and cardanolide series. Their ring system may contain further substituents, more especially in one Or several of the positions 1 to 5, 7 to 9, 11, 12, 14 to 17 and 19 to 21, such as functionally converted hydroxyl or free or functionally converted oxo groups, hydrocarbon radicals, which latter may also be attached in the 60t-POSltiOl'l, and/or halogen atoms. The term functionally converted hydroxy and oxo groups? designates esterified or etherified hydroxy groups or ketalized oxo groups. Compounds containing oxo groups may also be converted into enol derivatives, such as enol ethers or enol esters. Furthermore the new compounds may contain double bonds or oxido groups, for example in positions 4:5, 9:11 or 16:17.

Especially important starting materials are 3-oxygenated 5a-halogen-6a-hydroxy-androstanes, -pregnanes and -spirostanes, which contain advantageously in position 3 an acylated hydroxyl or ketalized oxo group. The androstane compounds may be further substituted especially in the Hot-position by a lower alkyl, alkenyl or alkinyl group and in l7B-position by a free or esterified hydroxyl group .or by a 17-oxo-group. The pregnane compounds may especially be substituted in the ZO-(and 11-) position by an oxo group or an esterified hydroxyl group and in 17a-position by an acyloxy group.

The acyloxy radicals mentioned above, representing esterified hydroxyl groups, are more especially those of aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids containing at most carbon atoms, such as for example formic, acetic, propionic, butyric, valeric, trimethylacetic, caproic, oenanthic, decanoic, trifluoracetic, carbonic, monomethylor ethylester, hexahydrobenzoic, cyclopentyl-propionic, phenyl-propionic, benzoic or furoic acid. The halogen atoms mentioned are fluorine, chlorine or bromine, in the Set-position especially chlorine or bromine, and the lower alkyl, alkenyl or alkinyl radicals are such as .contain at most 7 carbon atoms,for example methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl, vinyl, allyl, methallyl, ethinyl or Z-methyl-ethinyl, 2-ch1oroethinyl and Z-trifiuoromethyl-ethinyl.

Ketalized oxo groups are for examplelower alkylenedioxy groups, such as ethylenedioxy or propylenedioxy groups and etherified hydroxy groups are for example lower alkoxy groups, such as methoxy, ethoxy or propoxy groups or the tetrahydro-pyranyloxy group.

Specific starting materials are e.g. the following compounds:

3B-acetoxy-5a-chloroor -bromo-6B-hydroxy-spirostane,

SB-acetoXy-Sa-chloroor -bromo-6,8-hydroxy-17-oxoandrostane,

3B:17fi-diacetoxy-5u-chloroor -br0mo-65-hydroxyandrostane,

3/3:17B-diacetoxy-5a-chloroor -bromo-6,6-hydroxy- 17a-methyl-androstane,

3 fl-acetoxy-S a-chloro-6 8-hydr'oxy-16 17 a-oxido-20-oxopregnane,

the 17 :20,20:ZI-bis-methylenedioxy compound of 35- acetoxy-S u-chloro-ofiz 17 cc 2 1 -trihydr.oxy-20-oxopregnane,

35:ZO/B-diacetoxy-Sa-chloro-6,8-hydroxy-pregnane,

3 ,8-acetoxy-5a-chloro-6,6-hydroxyl 6: 170L-OXidO2 O-oxopregnane,

the 18 :20-lactone of 35-acetoxy-5a-chloro-65:205-

dihydroxy-pregnane-lS-acid,

3fi-acetoxy-5a-chloro-6B-hydr0xy-20-oxo-pregnane,

3,8-117a-diacetoxy-5a-chloro-6fi-hydroxy-20-oxopregnane,

3 ,B-acetoxy-Su-chloro-6/8-hydroxy-l7ot-valerianoyloxy- 20-oxo-pregnane,

3fl-acetoxy-5a-chloro-6fi-hydroxy-17ct-methoxy-20-oxopregnane or 3;?3:11a:ZOB-triacetoxy-Sa-chloro-6fi-hydroxy-pregnane.

For the production of the 19-nor-steroids the 65:19- oxido-steroids of the present invention are converted into A -3-oxo-19-hydroxy-steroids, from which the angular substituent is eliminated in known manner, preferably after oxidation to an aldehyde or acid function. The transformation of the 5a-halogen-6B:19-oxido-steroids or of the A -3-oxo-6 8:19-oxido-steroids into A -19-hydroxyand A 3-oxo:19-hydroxy-steroids respectively is effectedunder the influence of a reducing agent, for example with, zinc and acetic acid. These processes are described in our copending application Ser. No. 122,655, filed July 10, 1961 (now US. Patent No. 3,067,198), and Ser. No. 122,656, filed July 10, 1961 (now US. Patent No. 3,077,482), by Albert Wettstein, et al.

6fizl9-oxido-steroids with a hydrogen atom in 511- positioncan be transformed into A -l9-hydroxy-steroids by acylolytic opening of the oxide bridge, for example with t acetic anhydride and p-toluene sulfonic acid or boron trifiuoride. Any 6-a-cyloxy-steroid formed in this reaction can then be hydrolyzed to a 6-hydroxy steroid from which water is eliminated in known manner. A -3:19dihydroxysteroids are converted into A -3-oxo-19-nor-steroids by oxidation under the Oppenauer conditions, i.e. with aluminum-isopropoxide and cyclohexanone in boiling toluene. The following examples illustrate the invention. The

temperatures are given in centigrade.

Example 1 A mixture of 1.0 gram of calcium carbonate, 3.0 grams of lead tetraacetate and cc. of methyl cyclohexane is heated for 15 minutes at about 100 C. 373 mg. of 3,8- acetoxy-5a-chloro-6fi-hydroxy-cholestane are added and the reaction mixture is refluxed for another 3 hours with stirring. The cooled solution isfreed from inorganic salts, the residue washed exhaustively with absolute ether.

melting at 134139 C. From the mother liquor another;

34 mg. of a slightly less pure product melting at 129-132 C. can be isolated.

Example 2 2.5 grams of calcium carbonate and 6.0 grams of lead tetraacetate are heated in 200 cc. of cyclohexane. To the boiling solution there are added 950 mg. of 3:/3:17B-diacetoxy-Su-chloro-6/3-hydroxy-androstane and the solution is maintained at the boil for 14 hours with stirring. The reaction solution is cooled, freed by filtration from undissolved salts, washed with ether and the filtrate extracted with water. From the dried organic solution there are obtained by evaporation under a water-jet vacuum 1.17 grams of a residue. The latter is purified by chromatography on aluminum oxide. The product is eluted with benzene and crystallized from alcohol to yield 35:17pdiacetoxy 5a chloro 65: 19 oxido androstane melting at 160-161" C. Example 3 4 grams of 3 3:ZOB-diacetoxy-Sa-chloro-6fl-hydroxy-5upregnane are added to a suspension of 7.5 grams of calcium carbonate and 20 grams of lead tetraacetate in 800 cc. of methyl-cyclohexane, and the reaction mixture is boiled under reflux with stirring for 3 /2 hours. The reaction mixture is cooled, the insoluble salts are filtered off with suction and the precipitate Washed with ether. The filtrate is washed with potassium iodide and dilute sodium thiosulfate solution, dried and evaporated under a water-jet vacuum. There are obtained 5.2 grams of a partially crystallized residue. By recrystallization from a mixture of acetone and hexane there are obtained 2.8 grams of 3B:ZOfi-diacetoxy-Sa-chloro-6fl: 19 oxido 51x pregnane melting at 148150 C.; optical rotation [a] =+25 (in chloroform).

Example 4 A suspension of 3.0 grams of lead tetraacetate and 1.4 grams of calcium carbonate are heated at the boil in 120 cc. of cyclohexane for 30 minutes. 600 mg. of 3132175- diacetoxy-Srr-bromo6B-hydroxy-androstane are then added and the boiling solution stirred for another 14 hours. The reaction solution is cooled and worked up as described in Example 2. There are obtained 820 mg. of crude product which is purified by chromatography on 20 grams of aluminum oxide, From the fractions eluted with benzenehexane mixture (1:1) and with benzene there are obtained by crystallization from a mixture of ether and hexane 250 mg. of 3/3:17 8-diacetoxy-5a-bromo-6fl:19- oxido-androstane melting at 178-180 C.; optical rotation [a] =5.4 (in chloroform).

Example 5 A mixture .of -2.0 grams of 35:llaz20p-triacetoxy-5achloro-6fl-hydroxypregnane and 500 cc. of cyclohexane with 15.0 grams of lead tetraacetate is boiled for 14 hours with stirring and under exclusion of moisture, then cooled. The undissolved salts are filtered oil and the filter cake is rinsed with ethylacetate. The filtrate is washed with water, dried and evaporated in a water-jet vacuum, to yield 2.328 grams of a partially crystalline residue which is dissolved in benzene, and the solution is filtered through 30 grams of alumina. The fractions eluted with a total of 600 cc. benzene yield on crystallization from ether+pentane 1.03 grams of 3,8:lluz20fl-triacetoxy-5occhloro-6B:19-oxidopregnane melting at 228-230 C. From the following fractions eluted with 200 cc. of a 1:1-mixture of benzene and ethyl acetate there are recovered by crystallization of the evaporation residue from ether 452 mg. of the 5a-chloro-6/3-hydroxy compound used as starting material.

The 3,8:1lou20l3 triacetoxy 5oz chloro 65 hydroxy-pregnane employed as starting material is prepared as follows: 18.71 grams of A -3-oxo-11a-acetoxy-20/3- hydroxypregnene are heated to boiling point in 100 cc. of isopropenyl acetate after adding 0.1 cc. of concentrated sulfuric acid. After one hour, cc. of solvent are distilled off, boiling is then continued for another hour under reflux and the solution is then evaporated in a water-jet vacuum after adding 500 mg. of anhydrous sodium acetate. The residue is taken up in methylene chloride and the solution is washed with water, dried and once more evaporated. From the crude product (21 grams), 13.66 grams of pure A -32llzxIZOB-tliQCfitOXY- pregnatriene having a melting point of 150 C. are obtained by crystallization from ether; [a] =144.3 (in chloroform); UV maximum at 235m (=19,500) IR bands inter alia at 5.77 (with shoulder at 5.68 1.) and 8.16;. (acetates), 9.76 1; 10.40 1 and 10.83

12.0 grams of this enol acetate are dissolved in 900 cc. of alcohol. A solution of 6.0 grams of sodium borohydride in 120 cc. of 70% aqueous alcohol is added to the solution, which has been cooled to +5 C., and the reaction mixture is allowed to stand for 3 days at 0 C. 10 cc. of glacial acetic acid are then dripped in while stirring and the reaction mixture is concentrated in a water-jet vacuum to about 100 cc., diluted with methylene chloride and washed with Water. 11.52 grams of a residue are obtained from the dried methylene chloride solution after evaporation and from this 9.78 grams of pure A -3B-hydroxy-1laz20p-diacetoxypregnene can be isolated by crystallization from ether. The compound, after being dissolved once more in methanol and allowed to crystallize, melts at 162165 C.; [cc] =69.6 (in chloroform); IR bands inter alia at 2.74,u (OH), 578 and 809a (acetates); 9.76 and 10.45u.

9.78 grams of this compound are allowed to stand overnight at room temperature in 50 cc. of pyridine and 30 cc, of acetic anhydride. The reaction mixture is then evaporated to dryness in a water-jet vacuum and the residue is crystallized from aqueous methanol. 10.1 grams of A -3B:11uz20fl-triacetoxypregnene having a melting point of 141143 C. are obtained; [a] =-59.4 (in chloroform). IR bands inter alia at 5.78 and 8.09;. (acetates), 9.76 1; 10.44 and 10.93n.

3.0 grams of A 813:11a:ZOB-triacetoxypregnene are dissolved in 180 cc. of ether. After adding 180 cc. f Water and 3.0 grams of chlorinated lime, the reaction solution is thoroughly stirred and 2.1 cc. of glacial acetic acid are then added. The two phases are then well mixed for 40 minutes with a vibromixer, 50 cc. of 2% sodium thiosulfate solution and 50 cc. of 5% potassium iodide solution are then added, separation is carried out and the organic solution is washed several times with Water. 1.78 grams of 35:11a:20,8-triacetoxy-5a-chloro-6/3-hydroxypregnane having a melting point of 225227 C. are obtained from the evaporation residue (3.417 grams) by crystallization from ether; [a] =43.2O (in chloroform); IR bands inter alia at 2.74; (OH); 5.78,u a 8.09, (acetates); 9.30 9.56;; 9.75n and 10.45,u.

Example 6 A suspension of 10.0 g. of 3[3-acetoxy-5a-chloro-65-- hydroxy-17-oxo-androstane and 65 g. of lead tetraacetate in 3.3 liters of cyclohexane is stirred under reflux for 14 hours. The cooled solution is filtered, the residue washed with ether and the filtrate is shaken with dilute sodium thiosulfate solution and with Water. An evaporation of the organic solution there are obtained 12.1 g. of a crude residue from which by recrystallization from ether-methanol 6.3 g. of 3B-acetoxy-5wchloro-6fi:19- oxido-17-oxo-androstane melting at 180-182.

In a completely analogous manner from 2.5 g. of 3,8- acetoxy-Sa-bromo-6fi-hydroxy-17-oxo-androstane 1.51 g. of 3B-acetoXy-5a-bromo-6B:19-oxido-17-oxo-androstane of melting point 174l78/184-187 are obtained.

Example 7 2.5 grams of 3fi-acetoxy-5a-chloro-6,6-hydroxy-20-oxopregnane, 5.0 grams of calcium-carbonate and 10 grams of lead tetraacetate are stirred in 450 ml. of cyclohexane and the mixture is kept boiling for 16 hours, then cooled and filtered. The filtrate is washed with dilute sodium sulfite solution and with water, dried and evaporated under reduced pressure. By crystallization of the crude product from ether 1.47 g. of 3,13-flC6tOXY-5a-Chl0l0- 65:19-oxido-20-oxo-pregnane melting at 153 is ob- 7 tained; [a] =+65 (in chloroform). IR bands at 5.78, 5.88, 6.70, 8.13, 9.12, 9.66, 10.60, 10.86 and.11.75;i.

In an analogous mariner there are obtained from 3fizl7a-diacetoxy 50c chloro-6fl-hydroxy-20-0Xopregnane the 3,8: l7u-diacetoxy-5a-chloro-6fi: l9-oxid0- 20-oxo-pregnane melting at 187-187.5 C.,

from 3[3-21C6tOXY-5oz-Chl0r0-6fi-hYClIOXY-17a-Val6ri3ny1OXy- 20-oxo-pregnane the 3B-acetoxy-5a-chloro-6fi:19-oxidol7a-valerianyloxy-ZO:oxo-pregnane, and

from 3fi-acetoxy-Sa-chloro-6B-hydroxy-17a-rnethoxy-20- oXo-pregnane the 3B-acetoxy-5a-chloro-6B:19-0Xido- 17a-methoxy-20-oxopregnane.

The chlorohydrin used as starting material is prepared in the following manner: A solution of 150 grams of pregnenolone acetate in liters of ether is treated with 150 grams of chlorinated lime (containing 30%. of active chlorine and 8.2 liters of water and the reaction mixture is vigorously stirred. After 5 minutes 105 cc. of glacial acetic acid and after another 25 minutes 500 cc. of potassium iodide solution of 10% strength are added. Finally, the aqueous phase is separated, and the ethereal solution is washed with sodium thiosulfate solution of 10% strength, dilute sodium bicarbonate solution and with water, dried and evaporated in a water-jet vacuum. The residue is treated with 800 cc. of acetone and kept overnight at 0 C., to yield 47.5 grams, and from the mother liquor another 58 grams, of 3[3-acetoxy-5u-chloro-6B-hydroxy-ZO-oxo-pregnane which melts at 196 to 197 C. after recrystallization from acetone. Optical rotation [u] =+25.5 (in chloroform). The infra-red spectrum of the compound displays bands, inter alia, at 2.75, 5.78, 5.88, 8.12, 8.68, 9.68 and 9.72

In an analogous manner addition of hypochlorous acid on to the 17a-acetoxy-pregnenolone acetate yields 3 5: 17adiacetoxy-5a-chloro-6B-hydroXy-20-oxo-pregnane.

What is claimed is:

1. Processfor the manufacture of 6,8:19-oXido-steroids selected from the group consisting of those of the androstane, pregnane, cholane, cholestane, spirostane, stigmastane and cardanolide series, consisting in treating a 19- unsubstituted Sat-halogeno-Gfi-hydroxy-steriod selected from the group consisting of one of the androstane, pregnane, cholane, chloestane, spirostane, stigmastane and cardanolide series with a heavy metal acylate derived from a carboxylic acid having 1 to carbon atoms having an oxidizingaction to produce 5oc-halogens-6fizl9- oxido steroids.

2. Process according to claim 1, wherein the heavy metal acylate used is a lead tetraacylate.

of the formula Hal wherein R stands for an acyloxy radical, R stands for a member selected from the group consisting of hydrogen, 0x0 and acyloxy together with hydrogen, R stands for a member selected from the group consisting of 0x0, acyloxy together with hydrogen, acyloxy together with lower alkyl, acyloxy together with.

lower alkenyl, acyloxy together with acetyl, hydrogen together with acetyl and hydrogen together with acyloxy-acetyl, and

Hal stands for a halogen atom with a molecular weight above 30, said acyloxy in each instance being derived from a carboxylic acid having 1 to 15 carbon atoms is used as starting material.

References Cited UNITED STATES PATENTS 9/1961 Ringold et al 260239.55 5/1962 Ringold ct al 260239.55

ELBERT L. ROBERTS, Primary Examiner.

LEWIS GO'ITS, Examiner. 

1. PROCESS FOR THE MANUFACTURE OF 6B:19-OXIDO-STEROIDS SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE ANDROSTANE, PREGNANE, CHOLANE, CHOLESTANE, SPIROSTANE, STIGMASTANE AND CARDANOLIDE SERIES, CONSISTING IN TREATING A 19UNSUBSTITUTED 5A-HALOGENO-6B-HYDROXY-STERIOD SELECTED FROM THE GROUP CONSISTING OF ONE OF THE ANDROSTANE, PREGNANE, CHOLANE, CHLOESTANE, SPIROSTANE, STIGMASTANE AND CARDANOLIDE SERIES WITH A HEAVY METAL ACYLATE DERIVED FROM A CARBOXYLIC ACID HAVING 1 TO 15 CARBON ATOMS HAVING AN OXIDIZING ACTION TO PRODUCE 5A-HALOGENS-6B:19OXIDO STEROIDS. 